Problem. This project will investigate the cellular and molecular events that link local infection in a primary body space with systemic consequences and injury to distant organs. The major hypothesis is that a three compartment model best explains the responses of humans to bacteria and their products. In this model, bacteria enter an initial compartment (e.g., lungs or abdominal cavity), and local interactions between bacteria and host effector systems govern whether bacteria are effectively eliminated. When first compartment responses are ineffective, responses occur in the second "systemic" compartment. When the second compartment responses are severe, responses occur in the third compartment (distant organs). In the lungs these responses include injury to the epithelial barrier and sustained loss of function. We will investigate important questions that relate to understanding this model. The major long-term goal is to understand how responses in the second and third compartments can be minimized without adversely affecting bacterial elimination in the first compartment. Specific Aims. 1) to investigate the "first compartment" responses in the lungs and the peritoneal cavity, in order to determine why the "first compartment" responses differ in each of these two sites; 2) to investigate the critical inter-relationships between the first compartment and the second compartment inflammatory responses; 3) to investigate the mechanisms by which injury occurs to the lung epithelium in the third compartment; 4) to investigate strategies that will protect the third compartment without adversely affecting antibacterial responses in the first compartment. Experimental approach. We will study rabbits with pneumonia or peritonitis due to E. coli, and follow them for up to 24 hours after infection. Responses in the first compartment will be compared with systemic physiologic and inflammatory response variables, and measurements of functional and anatomic integrity of the third compartment (lungs). New strategies to protect the third compartment without compromising antibacterial defenses in the first compartment will be investigated. Significance. These studies will provide information about the relationship between local and systemic responses and lung injury in sepsis, and will help to determine whether the best approach to prevention and treatment of septic complications is to focus on the specific organism (e.g., better antibiotics), or on interfering with the host response (e.g., better anti-inflammatory therapy), or both.